Abstract
LETM1 is a mitochondrial inner membrane protein that is required for maintaining the mitochondrial morphology and cristae structures, and regulates mitochondrial ion homeostasis. Here we report a role of LETM1 in the organization of cristae structures. We identified four amino acid residues of human LETM1 that are crucial for complementation of the growth deficiency caused by gene deletion of a yeast LETM1 orthologue. Substituting amino acid residues with alanine disrupts the correct assembly of a protein complex containing LETM1 and prevents changes in the mitochondrial morphology induced by exogenous LETM1 expression. Moreover, the LETM1 protein changes the shapes of the membranes of in vitro-reconstituted proteoliposomes, leading to the formation of invaginated membrane structures on artificial liposomes. LETM1 mutant proteins with alanine substitutions fail to facilitate the formation of invaginated membrane structures, suggesting that LETM1 plays a fundamental role in the organization of mitochondrial membrane morphology.
Highlights
LETM1 is a mitochondrial inner membrane protein that is required for maintaining the mitochondrial morphology and cristae structures, and regulates mitochondrial ion homeostasis
Two kinds of LETM1 mutant proteins in which four amino acid residues were altered lost the ability to change the shapes of proteoliposomes, suggesting that LETM1 is involved in forming the mitochondrial membrane morphology independent of mitochondrial ion homeostasis
Complementation assays using yeast cells demonstrated that the LETM domain, but not the leucinezipper and EF-hand domains, was required to suppress the growth defect of the yeast mdm[38] gene-deletion mutant, indicating that the well-known characteristic motifs of LETM1 are not essential for LETM1 functions in yeast cell growth on a non-fermentable carbon source
Summary
LETM1 is a mitochondrial inner membrane protein that is required for maintaining the mitochondrial morphology and cristae structures, and regulates mitochondrial ion homeostasis. LETM1 mutant proteins with alanine substitutions fail to facilitate the formation of invaginated membrane structures, suggesting that LETM1 plays a fundamental role in the organization of mitochondrial membrane morphology. In contrast to the widespread physiologic roles of LETM1 in mitochondrial events, changes in mitochondrial morphology, i.e., mitochondrial swelling and aberrant cristae structures, are common features resulting from the downregulation of LETM1 orthologs[3,4,5,7,8,9,10]. Two kinds of LETM1 mutant proteins in which four amino acid residues were altered lost the ability to change the shapes of proteoliposomes, suggesting that LETM1 is involved in forming the mitochondrial membrane morphology independent of mitochondrial ion homeostasis
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